Epithelial ovarian cancer (EOC) is the gynecological
disease with the highest death rate. We applied an
automatic class discovery procedure based on gene
expression profiling to stages III–IV tumors to search
for molecular signatures associated with the biological
properties and progression of EOC. Using a complementary
DNA microarray containing 4451 cancer-related,
sequence-verified features, we identified a subset of EOC
characterized by the expression of numerous genes related
to the extracellular matrix (ECM) and its remodeling,
along with elements of the fibroblast growth factor 2
(FGF2) signaling pathway. A total of 10 genes were
validated by quantitative real-time polymerase chain
reaction, and coexpression of FGF2 and fibroblast growth
factor receptor 4 in tumor cells was revealed by
immunohistochemistry, confirming the reliability of gene
expression by cDNA microarray. Since the functional
relationships among these genes clearly suggested involvement
of the identified molecular signature in processes
related to epithelial–stromal interactions and/or epithelial–
mesenchymal cellular plasticity, we applied supervised
learning analysis on ovarian-derived cell lines
showing distinct cellular phenotypes in culture. This
procedure enabled construction of a gene classifier able
to discriminate mesenchymal-like from epithelial-like
cells. Genes overexpressed in mesenchymal-like cells
proved to match the FGF2 signaling and ECM molecular
signature, as identified by unsupervised class discovery on
advanced tumor samples. In vitro functional analysis of
the cell plasticity classifier was carried out using two
isogenic and immortalized cell lines derived from ovarian
surface epithelium and displaying mesenchymal and
epithelial morphology, respectively. The results indicated
the autocrine, but not intracrine stimulation of mesenchymal
conversion and cohort/scatter migration of cells by
FGF2, suggesting a central role for FGF2 signaling in the
maintenance of cellular plasticity of ovary-derived cells
throughout the carcinogenesis process. These findings
raise mechanistic hypotheses on EOC pathogenesis and
progression that might provide a rational underpinning for
new therapeutic modalities.
